Concomitant T790M mutation and small‐cell lung cancer transformation after acquired resistance to epidermal growth factor receptor‐tyrosine kinase inhibitor

Fujita, Kohei; Kim, Young Hak; Yoshizawa, Akihiko; Mio, Tadashi; Mishima, Michiaki

doi:10.1002/rcr2.206

Cited by 7 publications

(5 citation statements)

References 7 publications

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“…However, when resistance occurs in the form of a transformation, the T790M-mutation tends not to arise in the same malignancy indicating their rare concurrent pattern. 10 The same reciprocal interaction was explained by Suda et al in their scientific report. They analyzed nine EGFR-TKI-refractory metastatic lesions after a patient died with metastatic NSCLC.…”

Section: Discussionsupporting

confidence: 60%

“…11 Despite the fact that this is a predominant pattern, Fujita et al have recently reported the concurrent existence of T790M-mutation and a SCLC transformation following TKI-resistance. 10 Additionally, one author proposed the role of SCLC tumor markers (pro-gastrin-releasing peptide and neuron-specific enolase) during a TKI-resistance of SCLC as it might be helpful in early detection of transformation. 12 It is also noteworthy that lung cancer is not the only malignancy involving this transformation.…”

Section: Discussionmentioning

confidence: 99%

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Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?

Wahab

Kesari

Chaudhary

et al. 2017

Cancer Biology & Therapy

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Lung cancer is one of the leading causes of cancer-related mortality and is categorized into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). We present a patient with epidermal growth factor receptor (EGFR)-mutant-NSCLC who developed metastatic SCLC after initial therapy with second-generation EGFR-tyrosine kinase inhibitor, afatinib. A 65-year-old male non-smoker was diagnosed with adenocarcinoma of the right lung, stage IVA (M1a). Due to tumor positivity for EGFR-Exon 19 deletion, the patient was started on oral afatinib, which resulted in a partial response. After ten months of treatment, he presented in the office with abdominal pain, distension, weight loss and jaundice. He had diffuse skeletal and hepatic metastases on PET/CT scan with interval progression of his cancer. Although the recurrence of lung adenocarcinoma was suspected, the patient was diagnosed with SCLC on liver biopsy. He received two cycles of chemotherapy and died due to pneumonia and sepsis.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?

Wahab

Kesari

Chaudhary

et al. 2017

Cancer Biology & Therapy

View full text Add to dashboard Cite

show abstract

“…After the tumors became refractory to afatinib, we detected the EGFR-T790M mutation by liquid biopsy and started osimertinib treatment as the third choice of EGFR-TKI. Although several cases have reported refractory tumors, including the coexistence of EGFR-T790M mutation and SCLC transformation after acquiring resistance to EGFR-TKI [ [10] , [11] , [12] ], this is the first report of metachronous resistances to targeted agents diagnosed by repeated genetic testing and successful sequential therapies for the management of tumor growth. Moreover, to our knowledge, this is also the first report of the detection of EGFR-T790M mutation by liquid biopsy after refractory tumors with SCLC transformation.…”

Section: Discussionmentioning

confidence: 99%

Successful sequential treatment of refractory tumors caused by small cell carcinoma transformation and EGFR-T790M mutation diagnosed by repeated genetic testing in a patient with lung adenocarcinoma harboring epidermal growth factor receptor mutations: A case report

Nishioka

Yamada

Harita

et al. 2018

Respiratory Medicine Case Reports

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NSCLC patients with EGFR mutations respond to EGFR-TKIs; however, the management of refractory tumors to EGFR-TKIs remains unclear. We demonstrated that repeated genetic testing might be useful for detecting resistance mechanisms as well as for decision-making in EGFR mutated NSCLC patients, following the emergence of resistance to the initial EGFR-TKIs.A 69-year-old man was diagnosed with lung adenocarcinoma with an EGFR exon 19 deletion. After tumor re-growth treated with erlotinib and chemotherapy, he was diagnosed with an SCLC transformation and administered chemotherapy to treat the SCLC. After the resistance of chemotherapy, the EGFR-T790M mutation by liquid biopsy was detected and treated him with osimertinib, which resulted in a clinical response.

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“…Activating mutations in EGFR (epidermal growth factor receptor) and KRAS (a member of the RAS/MAPK pathway) occur in about 10-30% of NSCLC [6]. Although EGFR-Tyrosine kinase inhibitors (TKIs) are an established treatment for patients with a confirmed EGFR mutation [7], most patients develop drug resistance over time [8,9]. Also, patients with a KRAS mutation do not have a targeted therapy available to them [10].…”

Section: Introductionmentioning

confidence: 99%

PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies

et al. 2019

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Signal Transducers and Activators of Transcription-3 (STAT3), a potent oncogenic transcription factor, is constitutively activated in lung cancer, but mutations in pathway genes are infrequent. Protein Tyrosine Phosphatase Receptor-T (PTPRT) is an endogenous inhibitor of STAT3 and PTPRT loss-of-function represents one potential mechanism of STAT3 hyperactivation as observed in other malignancies. We determined the role of PTPRT promoter methylation and sensitivity to STAT3 pathway inhibitors in non-small cell lung cancer (NSCLC). TCGA and Pittsburgh lung cancer cohort methylation data revealed hypermethylation of PTPRT associated with diminished mRNA expression in a subset of NSCLC patients. We report frequent hypermethylation of the PTPRT promoter which correlates with transcriptional silencing of PTPRT and increased STAT3 phosphorylation (Y705) as determined by methylation-specific PCR (MSP) and real time quantitative reverse transcription (RT)-PCR in NSCLC cell lines. Silencing of PTPRT using siRNA in H520 lung cancer cell line resulted in increased pSTAT3 Tyr705 and upregulation of STAT3 target genes such as Cyclin D1 and Bcl-X L expression. We show this association of PRPRT methylation with upregulation of the STAT3 target genes Cyclin D1 and Bcl-X L in patient derived lung tumour samples. We further demonstrate that PTPRT promoter methylation associated with different levels of pSTAT3 Ty705 in lung cancer cell lines had selective sensitivity to STAT3 pathway small molecule inhibitors (SID 864,669 and SID 4,248,543). Our data strongly suggest that silencing of PTPRT by promoter hypermethylation is an important mechanism of STAT3 hyperactivation and targeting STAT3 may be an effective approach for the development of new lung cancer therapeutics.

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Concomitant T790M mutation and small‐cell lung cancer transformation after acquired resistance to epidermal growth factor receptor‐tyrosine kinase inhibitor

Cited by 7 publications

References 7 publications

Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?

Sequential occurrence of small cell and non-small lung cancer in a male patient: Is it a transformation?

Successful sequential treatment of refractory tumors caused by small cell carcinoma transformation and EGFR-T790M mutation diagnosed by repeated genetic testing in a patient with lung adenocarcinoma harboring epidermal growth factor receptor mutations: A case report

PTPRT epigenetic silencing defines lung cancer with STAT3 activation and can direct STAT3 targeted therapies

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